Iodine-mediated electrophilic cyclization of 2-alkynyl-1-methylene azide aromatics leading to highly substituted isoquinolines and its application to the synthesis of norchelerythrine.
The reaction of 2-alkynyl-1-methylene azide aromatics 1 with iodine and/or other iodium donors, such as the Barluenga reagent (Py2IBF4/HBF4) and NIS, gave highly substituted cyclization products, namely, the 1,3-disubstituted 4-iodoisoquinolines 2, in good to high yields. Not only simple 2-alkynyl benzyl azides 1a-j and their substituted analogues 1k-u and 6 but also heteroaromatic analogues, including pyridine 8, pyrroles 10a-c, furane 10d, and thiophenes 10e-g, gave the corresponding isoquinoline derivatives in excellent to allowable yields. Electron-donating and electron-accepting substituents on the aromatic ring were equally tolerated, and either acidic or basic (or even neutral) reaction conditions, depending on the reactivity of the substrate, could be applied to smoothly convert the azide starting materials into the desired isoquinoline products in moderate to good yields. Limits were found only in connection with the substituent at the alkyne terminus, where electron-neutral or electron-donating substituents are clearly favored. The iodine-mediated electrophilic cyclization of 1 most probably proceeds through the iodonium ion intermediate 4 followed by nucleophilic cyclization of the azide and subsequent elimination of N2. This new methodology was successfully applied to the short synthesis of norchelerythrine.
Fischer
Dirk
D
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan.
Tomeba
Hisamitsu
H
Pahadi
Nirmal K
NK
Patil
Nitin T
NT
Huo
Zhibao
Z
Yamamoto
Yoshinori
Y
D001386:Azides / Q000737:chemistry*; D053119:Benzophenanthridines / Q000138:chemical synthesis* / Q000737:chemistry; D002384:Catalysis; D003500:Cyclization; D004583:Electrons; D007455:Iodine / Q000737:chemistry*; D007546:Isoquinolines / Q000737:chemistry*; D015394:Molecular Structure; D010777:Photochemistry
D001386:Azides; D053119:Benzophenanthridines; D007546:Isoquinolines; D007455:Iodine; C016299:chelerythrine; C039109:isoquinoline